Relationship between CYP2D6 Genotype and Haloperidol Pharmacokinetics and Extrapyramidal Symptoms in Healthy Volunteers

• Casey DE . Neuroleptic-induced acute extrapyramidal syndromes and tardive dyskinesia. Psychiatr. Clin. North Am.16 , 589–610 (1993).
   PubMed Web of Science ®Google Scholar
• Doddi S , RifkinA, KarajgiB et al. Blood levels of haloperidol and clinical outcome in schizophrenia. J. Clin. Psychopharmacol. 14 , 187–195 (1994).
   PubMed Web of Science ®Google Scholar
• Forsman A , OhmanR. Studies on serum protein binding of haloperidol. Curr. Ther. Res. Clin. Exp.21 , 245–255 (1977).
   PubMed Web of Science ®Google Scholar
• Zhou SF . Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. Clin. Pharmacokinet.48 , 689–723 (2009).
   PubMed Web of Science ®Google Scholar
• Jaen JC , CapratheBW, PugsleyTA et al. Evaluation of the effects of the enantiomers of reduced haloperidol, azaperol, and related 4-amino-1-arylbutanols on dopamine and σ receptors. J. Med. Chem. 36 , 3929–3936 (1993).
   PubMed Web of Science ®Google Scholar
• Inaba T , KovacsJ. Haloperidol reductase in human and guinea pig livers. Drug Metab. Dispos.17 , 330–333 (1989).
   PubMed Web of Science ®Google Scholar
• Tyndale RF , KalowW, InabaT. Oxidation of reduced haloperidol to haloperidol: involvement of human P450IID6 (sparteine/debrisoquine monooxygenase). Br. J. Clin. Pharmacol.31 , 655–660 (1991).
   PubMed Web of Science ®Google Scholar
• Llerena A , DahlML, EkqvistB et al. Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype: increased plasma levels of the reduced metabolite in poor metabolizers. Ther. Drug Monit. 14 , 261–264 (1992).
   PubMed Web of Science ®Google Scholar
• Llerena A , AlmC, DahlML et al. Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype. Ther. Drug. Monit. 14 , 92–97 (1992).
   PubMed Web of Science ®Google Scholar
• Suzuki A , OtaniK, MiharaK et al. Effects of the CYP2D6 genotype on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese schizophrenic patients. Pharmacogenetics 7 , 415–418 (1997).
   PubMedGoogle Scholar
• Mihara K , SuzukiA, KondoT et al. Effects of the CYP2D6*10 allele on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia. Clin. Pharmacol. Ther. 65 , 291–294 (1999).
   PubMed Web of Science ®Google Scholar
• Brockmöller J , KirchheinerJ, SchmiderJ et al. The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment. Clin. Pharmacol. Ther. 72 , 438–452 (2002).
   PubMed Web of Science ®Google Scholar
• Park JY , ShonJH, KimKA et al. Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects. J. Clin. Psychopharmacol. 26 , 135–142 (2006).
   PubMed Web of Science ®Google Scholar
• Panagiotidis G , ArthurHW, LindhJD et al. Depot haloperidol treatment in outpatients with schizophrenia on monotherapy: impact of CYP2D6 polymorphism on pharmacokinetics and treatment outcome. Ther. Drug Monit. 29 , 417–422 (2007).
   PubMed Web of Science ®Google Scholar
• Pan L , BelpaireFM. In vitro study on the involvement of CYP1A2, CYP2D6 and CYP3A4 in the metabolism of haloperidol and reduced haloperidol. Eur. J. Clin. Pharmacol.55 , 599–604 (1999).
   PubMed Web of Science ®Google Scholar
• Someya T , SuzukiY, ShimodaK et al. The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: a preliminary study in a psychiatric population. Psychiatry Clin. Neurosci. 53 , 593–597 (1999).
   PubMed Web of Science ®Google Scholar
• Shimoda K , MoritaS, YokonoA et al. CYP2D6*10 alleles are not the determinant of the plasma haloperidol concentrations in Asian patients. Ther. Drug Monit.22 , 392–396 (2000).
   PubMed Web of Science ®Google Scholar
• Ohnuma T , ShibataN, MatsubaraY et al. Haloperidol plasma concentration in Japanese psychiatric subjects with gene duplication of CYP2D6. Br. J. Clin. Pharmacol. 56 , 315–320 (2003).
   PubMed Web of Science ®Google Scholar
• Nyberg S , FardeL, HalldinC et al. D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate. Am. J. Psychiatry 152 , 173–178 (1995).
   PubMed Web of Science ®Google Scholar
• Roh HK , ChungJY, OhDY et al. Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients. Br. J. Clin. Pharmacol. 52 , 265–271 (2001).
   PubMed Web of Science ®Google Scholar
• Chang WH , LamYW, JannMW et al. Pharmacokinetics of haloperidol and reduced haloperidol in Chinese schizophrenic patients after intravenous and oral administration of haloperidol. Psychopharmacology (Berl.) 106 , 517–522 (1992).
   PubMed Web of Science ®Google Scholar
• Lane HY , LinHN, HuOY et al. Blood levels of reduced haloperidol versus clinical efficacy and extrapyramidal side effects of haloperidol. Prog. Neuropsychopharmacol. Biol. Psychiatry 21 , 299–311 (1997).
   PubMed Web of Science ®Google Scholar
• Mas S , BernardoM, GassóP et al. A functional variant provided further evidence for the association of ARVCF with schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153 , 1052–1059 (2010).
   Google Scholar
• Mas S , GassòP, AlvarezS et al. Intuitive pharmacogenetics: spontaneous risperidone dosage is related to CYP2D6, CYP3A5 and ABCB1 genotypes. Pharmacogenomics J. 12 , 255–259 (2012).
   PubMed Web of Science ®Google Scholar
• Crescenti A , MasS, GassoP et al. Simultaneous genotyping of CYP2D6*3, *4, *5 and *6 polymorphisms in a spanish population through multiplex long-PCR and minisequencing multiplex sinfle base extension (SBE) analysis. Clin. Exp. Pharmacol. Physiol. 34 , 992–997 (2007).
   PubMed Web of Science ®Google Scholar
• Corripio I , FerreiraA, PortellaMJ et al. The role of striatal dopamine D2 receptors in the occurrence of extrapyramidal side effects: iodine-123-iodobenzamide single photon emission computed tomography study. Psychiatry Res. 201 , 73–77 (2012).
   PubMed Web of Science ®Google Scholar
• Simpson GM , AngusJW. A rating scale for extra-pyramidal side effects. Acta Psychiatr. Scand. Suppl.212 , 11–19 (1970).
   PubMedGoogle Scholar
• Barnes TR . A rating scale for drug-induced akathisia. Br. J. Psychiatry154 , 672–676 (1989).
   PubMed Web of Science ®Google Scholar
• Middelkoop HA , van Dam EM, Smilde-van den Doel DA et al. 45-hour continuous quintuple-site actimetry: relations between trunk and limb movements and effects of circadian sleep–wake rhythmicity. Psychophysiology34 , 199–203 (1997).
   PubMed Web of Science ®Google Scholar
• Ventura J , LukoffD, NuechterleinKH. Appendix 1: Brief Psychiatric Rating Scale Expanded Version (4.0) scales, anchor points, and administration manual. Int. J. Meth. Psychiatr. Res.3 , 227–243 (1993).
   Google Scholar
• Andreasen NC . Modified Scale for the Assessment of Negative Symptoms (SANS). University of Iowa Press, IA, USA (1984).
   Google Scholar
• Artaloytia JF , ArangoC, LahtiA et al. Negative signs and symptoms secondary to antipsychotics: a double-blind, randomized trial of a single dose of placebo, haloperidol, and risperidone in healthy volunteers. Am. J. Psychiatry 163 , 488–493 (2006).
   PubMed Web of Science ®Google Scholar
• Jaeger J , BitterI, CzoborP et al. The measurement of subjective experience in schizophrenia: the Subjective Deficit Syndrome Scale. Compr. Psychiatry 31 , 216–226 (1990).
   PubMed Web of Science ®Google Scholar
• Bond AJ , JamesDC, LaderMH. Sedative effects on physiological and psychological measures in anxious patients. Psychol. Med.4 , 374–380 (1974).
   PubMed Web of Science ®Google Scholar
• Burgyone K , AduriK, AnanthJ, ParameswaranS. The use of antiparkinsonian agents in the management of drug-induced extrapyramidal symptoms. Curr. Pharm. Des.10 , 2239–2248 (2004).
   PubMed Web of Science ®Google Scholar
• Shin JG , KaneK, FlockhartDA. Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol. Br. J. Clin. Pharmacol.51 , 45–52 (2001).
   PubMed Web of Science ®Google Scholar
• Ackenheil M , WeberK. Differing response to antipsychotic therapy in schizophrenia: pharmacogenomic aspects dialogues. Clin. Neurosci.6 , 71–77 (2004).
   Google Scholar
• Shim JC , KellyDL, KimYH et al. Fluoxetine augmentation of haloperidol in chronic schizophrenia. J. Clin. Psychopharmacol. 23 , 520–522 (2003).
   PubMed Web of Science ®Google Scholar
• LLerena A , BereczR, DoradoP et al. Determination of risperidone and 9-hydroxyrisperidone in human plasma by liquid chromatography: application to the evaluation of CYP2D6 drug interactions. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 783 , 213–219 (2003).
   PubMed Web of Science ®Google Scholar
• Walther S , HornH, KoschorkeP et al. Increased motor activity in cycloid psychosis compared to schizophrenia. World J. Biol. Psychiatry 10 , 746–751 (2009).
   PubMed Web of Science ®Google Scholar
• Kiang M , DaskalakisZJ, ChristensenBK et al. Actigraphic measurement of the effects of single-dose haloperidol and olanzapine on spontaneous motor activity in normal subjects. J. Psychiatry Neurosci. 28 , 293–299 (2003).
   PubMed Web of Science ®Google Scholar

▪ Website

• Typical Versus Atypical Antipsychotics; Occupation of Striatal Receptors and the Appearance of Extrapyramidal Symptomatology, in Healthy Volunteers (APSEP). http://clinicaltrials.gov/ct2/show/NCT01259973
   Google Scholar